Supramolecular Systems Capable of Bio-inspired Communication and Recognition

Supramolecular Chemistry is often inspired by the functionality and complexity of nature. Whilst great strides have been made towards achieving artificial analogues of biological molecular machines, synthetic systems have been unable to match the specificity and directionality vital to the concerted processes of biology. Here, I will develop new tools to endow artificial supramolecular systems with the functionality seen in their biological counterparts. In the first four years, I will create architectures with unprecedented target binding specificity, and systems able to transfer information across biologically-relevant membranes. In the following three years, I will collaboratively apply these in biological contexts, aiming to achieve long-term impact on biomedicine and synthetic biology by creating de novo catalytic enzyme analogues, enabling the design of synthetic cellular receptors, and generating targeted drug delivery vehicles. In the longer term, this proposal will provide new ways to repair and, eventually, replace, faulty biological systems, and so to treat intractable diseases. The complexity and functionality of biological systems is due to the information-richness of biomolecules, and their controlled distribution and motion. These properties allow demanding tasks to be completed; biomachines, such as ATP synthase, work in concert across membranes, maintaining homeostasis, and information-rich enzymes transform specific molecules using targeted interactions. In contrast, the current generation of supramolecular assemblies lack the targeted recognition present in nature, and are typically unable to work in concert, as their motion cannot be orientated. This research proposal will provide tools to bridge this gap, addressing unmet challenges in Supramolecular Chemistry. I will develop interlocked architectures whose localisation in membranes enables oriented motion, acting as novel analogues of transmembrane receptors such as GPCRs, and information-rich molecular capsules with targeted functions, able to mimic the binding specificity and catalytic function of enzymes. My proposal will, firstly, develop interlocked architectures that can embed into membranes (combining my expertise in artificial molecular machines and rotaxane formation, and expertise in membrane science at King's and the Crick) and transmit information from outside the compartment to the interior. This will enable modulation of the internal environment without the signal molecule having to pass the membrane, by physically coupling the two compartments. As such, I will create novel analogues of transmembrane signalling proteins. We will use this technology to create artificial analogues of cellular receptors, with potential applications in synthetic biology and the treatment of channelopathies such as Cystic Fibrosis and Dravet Syndrome. Secondly, this proposal will combine the information-density of biological systems with the well-defined cavity of metal-organic capsules to create supramolecular capsules with a ground-breaking array of functions, enabled by precise and targeted functionalisation of the capsule, exploiting my extensive experience of self-assembled architectures. My proposal comes at a critical juncture, seeking to address emerging challenges by creating programmable and information-rich supramolecular systems. This Fellowship will create supramolecular architectures with unprecedented specificity and controlled oriented directional motion, then work with collaborators to apply these in biological contexts, aiming to achieve long-term impact on biomedical science.